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The EGF(R) and VEGF(R) Pathways as Combined Targets for Anti-Angiogenesis Trials in Cancer Therapy

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Tumor Angiogenesis

Abstract

In tumor biology both the EGF(R) and the VEGF(R) pathway are constitutively activated due to genetic abnormalities and ongoing tumor-associated hypoxia. In addition, both pathways can be activated by anticancer therapies such as chemotherapy and radiotherapy, which contributes to the resistance to these treatments. Moreover, VEGF modulates EGFR signaling and EGF induces VEGF activity. Therefore, both pathways are logical targets for therapy, and because of their parallel and reciprocal activation, dual inhibition of the EGF(R) and VEGF(R) signaling makes sense. In this chapter we discuss the possibilities for integrated anti-angiogenesis therapy directed at these two biological systems.

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References

  • Akagi M, Kawaguchi M, Liu W, McCarty MF et al (2003) Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer 88:796–802

    Article  PubMed  CAS  Google Scholar 

  • Amin DN, Hida K, Bielenberg DR, Klagsbrun M (2006) Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res 66:2173–2180

    Article  PubMed  CAS  Google Scholar 

  • Arao T, Yanagihara K, Takigahira M, Takeda M et al (2006) ZD6474 inhibits tumor growth and intraperitoneal dissimination in a highly metastatic orthotopic gastric cancer model. Int J Cancer 118:483–489

    Article  PubMed  CAS  Google Scholar 

  • Arkonac BM, Foster LC, Sibinga NE, Patterson C et al (1998) Vascular endothelial growth factor induces heparinbinding epidermal growth factor-like growth factor in vascular endothelial cells. J Biol Chem 20:4400–4405

    Article  Google Scholar 

  • Baker CH, Kedar D, McCarthy MF, Tsan R et al (2002) Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated cells endothelial cells for therapy of human carcinomas. Am J Pathol 161:929–938

    PubMed  CAS  Google Scholar 

  • Bos R, van Diest PJ, de Jong JS, van der Groep P et al (2005) Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 46:31–36

    Article  PubMed  CAS  Google Scholar 

  • Bozec A, Formento P, Ciccolini J, Fanciullino R et al (2005) Response of endothelial cells to a dual tyrosine kinase receptor inhibition combined with irradiation. Mol Cancer Ther 4:1962–1971

    Article  PubMed  CAS  Google Scholar 

  • Bruns CJ, Harbison MT, Davis DW, Portera CA et al (2000) Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 6:1936–1948

    PubMed  CAS  Google Scholar 

  • Camp ER, Summy J, Bauer TW, Liu W et al (2005) Molecular mechanisms of resistance to therapies targeting the epidermal growth factor. Clin Cancer Res 11:397–405

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69[Suppl 3]:4–10

    Article  PubMed  CAS  Google Scholar 

  • Chakravarti A, Chakladar A, Delaney MA, Latham DE, Loeffler JS (2002) The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary glioblastoma cells in a RAS-dependent manner. Cancer Res 62:4307–4315

    PubMed  CAS  Google Scholar 

  • Checkley D, Tessier JJ, Kendrew J, Waterton JC, Wedge SR (2003) Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours. Br J Cancer 89:1889–1895

    Article  PubMed  CAS  Google Scholar 

  • Chung KY, Shia J, Kemeny NE, Shah M et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810

    Article  PubMed  CAS  Google Scholar 

  • Ciardiello F, de Vita F (2005) Epidermal growth factor receptor (EGFR) inhibitors in cancer therapy. Prog Drug Res 63:93–114

    Article  PubMed  CAS  Google Scholar 

  • Ciardiello F, Bianco R, Damiano V, Fontanini G et al (2000) Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6:3739–3747

    PubMed  CAS  Google Scholar 

  • Ciardiello F, Caputo R, Bianco R, Damiano V et al (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465

    PubMed  CAS  Google Scholar 

  • Ciardiello F, Bianco R, Caputo R, Caputo R et al (2004) Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res 10:784–793

    Article  PubMed  CAS  Google Scholar 

  • Damiano V, Melisi D, Bianco C, Raben D et al (2005) Cooperative antitumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma. Clin Cancer Res 11:5639–5644

    Article  PubMed  CAS  Google Scholar 

  • Dawson NA, Guo C, Zak R, Dorsey B et al (2004) A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. Clin Cancer Res 10:7812–7819

    Article  PubMed  CAS  Google Scholar 

  • Drevs J, Konerding MA, Wolloscheck T, Wedge SR et al (2004) The VEGF receptor kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma. Angiogenesis 7:347–354

    Article  PubMed  CAS  Google Scholar 

  • Du Manoir JM, Francia G, Man S, Mossoba M et al (2006) Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res 12:904–916

    Article  Google Scholar 

  • Ferrara N (2005) VEGF as therapeutic target in cancer. Oncology 69[Suppl 3]:11–16

    Article  PubMed  CAS  Google Scholar 

  • Frassoldati A, Adami F, Banzi C, Criscuolo M et al (1997) Changes of biological features in breast cancer cells determined by primary chemotherapy. Breast Cancer Res Treatment 44:185–192

    Article  CAS  Google Scholar 

  • Frederick B, Gustafson D, Bianco C, Ciardiello F et al (2006) ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinase activity in combination with radiotherapy. Int J Rad Oncol Biol Phys 64:33–37

    Article  CAS  Google Scholar 

  • Gianelli G, Azzariti A, Sgarra C, Porcelli L et al (2006) ZD6474 inhibits proliferation and invasion of human hepatocellular carcinoma cells. Biochem Pharmacol 71:479–485

    Article  CAS  Google Scholar 

  • Goldman CK, Kim J, Wong WL, King V et al (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4:121–133

    PubMed  CAS  Google Scholar 

  • Gunaratnam L, Morley M, Franovic A, de Paulsen N et al (2003) Hypoxia-inducible factor activates the transforming growth factor-alpha/ epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J Biol Chem 278:44966–44974

    Article  PubMed  CAS  Google Scholar 

  • Hainsworth JD, Sosman JA, Spigel DR, Schwert RC et al (2005) Treatment of metastatic renal carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23:7889–7896

    Article  PubMed  CAS  Google Scholar 

  • Herbst RS, Johnson DH, Mininberg E, Carbone DP et al (2005) Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:2544–2555

    Article  PubMed  CAS  Google Scholar 

  • Heymach JV (2005) ZD6474: clinical experience to date. Br J Cancer 92:S14–S20

    Article  PubMed  CAS  Google Scholar 

  • Hidalgo M (2003) Erlotinib: preclinical investigations. Oncology 17:11–16

    PubMed  Google Scholar 

  • Hirata A, Ogawa S, Kometani T, Kuwano T et al (2002) ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62:2554–2560

    PubMed  CAS  Google Scholar 

  • Huang SM, Li J, Harari PM (2002) Molecular inhibition of angiogenesis and metastatic potential in human squamous cell carcinomas after epidermal growth factor receptor blockade. Mol Cancer Ther 1:507–514

    PubMed  CAS  Google Scholar 

  • Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM et al (2003) Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J 17:1609–1621

    Article  PubMed  CAS  Google Scholar 

  • Janne PA, Gurubhagavatula S, Yeap BY, Lucca J et al (2004) Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on an expanded access study. Lung Cancer 44:221–230

    Article  PubMed  Google Scholar 

  • Jung YD, Mansfield PF, Akagi M, Takeda A et al (2002) Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 38:1133–1140

    Article  PubMed  CAS  Google Scholar 

  • Kedar D, Baker CH, Killion JJ, Dinney CP, Fidler IJ (2002) Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 8:592–600

    Google Scholar 

  • Kim S, Schiff BA, Yigitbasi OG, Doan D et al (2005) Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788. Mol Cancer Ther 4:632–640

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi S, Boggon TJ, Dayaram T, Janne PA et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    Article  PubMed  CAS  Google Scholar 

  • Laderoute KR, Grant TD, Murphy BJ, Sutherland RM (1992) Enhanced epidermal growth factor receptor synthesis in human squamous carcinoma cells exposed to low levels of oxygen. Int J Cancer 52:428–432

    Article  PubMed  CAS  Google Scholar 

  • Lamszus K, Brockmann MA, Eckerich C, Bohlen P et al (2005) Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin. Clin Cancer Res 11:4934–4940

    Article  PubMed  CAS  Google Scholar 

  • Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) Her2 (neu) signaling increases the rate of hypoxiainducible factor 1 alpha (HIF-1α) synthesis: novel mechanism for HIF-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004

    Article  PubMed  CAS  Google Scholar 

  • Matar P, Rojo F, Cassia R, Moreno-Bueono G et al (2004) Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefinitib (ZD1939) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 10:6487–6501

    Article  PubMed  CAS  Google Scholar 

  • McCarty MF, Wey J, Stoeltzing O, Liu W et al (2004) ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. Mol Cancer Ther 3:1041–1048

    PubMed  CAS  Google Scholar 

  • Miller KD, Trigo JM, Wheeler C, Barge A et al (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11:3369–3376

    Article  PubMed  CAS  Google Scholar 

  • Ongusaha PP, Kwak JC, Zwible AJ, Macip S et al (2004) HBEGF is a potent inducer of tumor growth and angiogenesis. Cancer Res 64:5283–5290

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly SM, Leonard MO, Kieran N et al (2006) Hypoxia induces epithelial amphiregulin gene expression in a CREB-dependent manner. Am J Physiol Cell Physiol 290: C592–C600

    Article  PubMed  CAS  Google Scholar 

  • Parikh AA, Liu WB, Fan F, Stoeltzing O et al (2003) Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma. Cancer 98:720–729

    Article  PubMed  CAS  Google Scholar 

  • Park YW, Younes MN, Jasser SA, Yigitbasi OG et al (2005) AEE788, a dual tyrosine kinase receptor inhibitor, induces endothelial cell apoptosis in human cutaneous squamous cell carcinoma xenografts in nude mice. Clin Cancer Res 11:1963–1973

    Article  PubMed  CAS  Google Scholar 

  • Perez-Soler R (2004) Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (Osi-774) in non-small-cell lung cancer. Clin Lung Cancer 6:S20–S23

    PubMed  CAS  Google Scholar 

  • Perez-Soler R, Piperdi B, Haigentz M, Ling YH (2004) Determinants of sensitivity to the EGFR TK inhibitor erlotinib (E) in a panel of NSCLC cell lines. Proc Am Soc Clin Oncol 7026

    Google Scholar 

  • Perrotte P, Matsumoto T, Inoue K, Kuniyasu H et al (1999) Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5:257–265

    PubMed  CAS  Google Scholar 

  • Petit AM, Rak J, Hung MC, Rockwell P et al (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/ neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523–1530

    PubMed  CAS  Google Scholar 

  • Qiu L, Di W, Jiang Q, Scheffler E et al (2005) Targeted inhibition of transient activation of the EGFR-mediated cell survival pathway enhances paclitaxel-induced ovarian cancer cell death. Int J Oncol 27:1441–1448

    PubMed  CAS  Google Scholar 

  • Rak J, Yu JL, Klement G, Kerbel RS (2000) Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Invest Dermatol Proc 5:24–33

    Article  CAS  Google Scholar 

  • Rich JN, Sathornsumetee S, Keir ST, Kieran MW et al (2005) ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clin Cancer Res 11:8145–8157

    Article  PubMed  CAS  Google Scholar 

  • Sandstrom M, Johansson M, Andersson U, Bergh Aet al (2004) The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model. Br J Cancer 91:1174–1180

    PubMed  CAS  Google Scholar 

  • Semino CE, Kamm RD, Lauffenburger DA (2006) Autocrine EGF receptor activation mediates endothelial cell migration and vascular morphogenesis induced by VEGF under interstitial flow. Exp Cell Res 312:289–298

    PubMed  CAS  Google Scholar 

  • Shaheen RM, Ahmad SA, Liu W, Reinmuth N et al (2001) Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85:584–589

    Article  PubMed  CAS  Google Scholar 

  • Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  PubMed  CAS  Google Scholar 

  • Sini P, Wyder L, Schnell C, Littlewood A et al (2005) The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade. Clin Cancer Res 11:4521–4532

    Article  PubMed  CAS  Google Scholar 

  • Sumitomo M, Asano T, Asakuma J, Asano T et al (2004) ZD1839 modulates paclitaxel response in renal cell cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway. Clin Cancer Res 10:794–801

    Article  PubMed  CAS  Google Scholar 

  • Swinson DE, Jones JL, Cox G, Richardson D et al (2004) Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathway. Int J Cancer 111:43–50

    Article  PubMed  CAS  Google Scholar 

  • Thaker PH, Yazici S, Nilsson MB, Yokoi K et al (2005) Antivascular therapy for orthotopic human ovarian carcinoma through blockade of the vascular endothelial growth factor and epidermal growth factor receptors. Clin Cancer Res 11:4923–4933

    Article  PubMed  CAS  Google Scholar 

  • Van Cruijsen H, Giaccone G, Hoekman K (2005) Epidermal growth factor receptor and angiogenesis: opportunities for combined anticancer strategies. Int J Cancer 118:883–888

    Article  CAS  Google Scholar 

  • Viloria-Petit AM, Kerbel RS (2004) Acquired resistance to EGF inhibitors: mechanisms and prevention strategies. Int J Radiat Oncol Biol Phys 58:914–926

    Article  PubMed  CAS  Google Scholar 

  • Viloria-Petit A, Crombet T, Jothy S, Hicklin D et al (2001) Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 61:5090–5101

    PubMed  CAS  Google Scholar 

  • Wedge SR, Kendrew J, Hennequin LF, Valentine PJ et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  PubMed  CAS  Google Scholar 

  • Waltenberger J, Mayr U, Pentz S, Hombach V (1996) Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94:1647–1654

    PubMed  CAS  Google Scholar 

  • Watwe V, Javle M, Lawrence D, Groth J et al (2005) Cyclooxygenase-2 (cox-2) levels before and after chemotherapy: a study in rectal cancer. Am J Clin Oncol 28:560–564

    Article  PubMed  Google Scholar 

  • Wild R, Dings RP, Subramanian I, Ramakrishnan S (2004) Carboplatin selectively induces the VEGF stress response in endothelial cells: potentiation of antitumor activity by combination treatment with antibody to VEGF. Int J Cancer 110:343–351

    Article  PubMed  CAS  Google Scholar 

  • Williams KJ, Telfer BA, Brave S, Kendrew J et al (2004) ZD6474, a potent inhibitor of vascular endothelial growth factor signaling, combined with radiotherapy: scheduledependent enhancement of antitumor activity. Clin Cancer Res 10:8587–8593

    Article  PubMed  CAS  Google Scholar 

  • Yang JC (2004) Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res 10:6367S–6370S

    Article  PubMed  CAS  Google Scholar 

  • Yano S, Muguruma H, Matsumori Y, Goto H et al (2005) Antitumor vascular strategy for controlling experimental metastatic spread of human small-cell lung cancer cells with ZD6474 in natural killer cell-depleted severe combined immunodeficient mice. Clin Cancer Res 11:8729–8798

    Article  Google Scholar 

  • Yazici S, Kim SJ, Busby JE, He J et al (2005) Dual inhibition of the epidermal growth factor and vascular endothelial growth factor phosphorylation for antivascular therapy of human prostate cancer in the prostate of nude mice. Prostate 65:203–215

    Article  PubMed  CAS  Google Scholar 

  • Yigitbasi OG, Younes MN, Doan D, Jasser SA et al (2004) Tumor cell and endothelial cell therapy of oral cancer by dual tyrosine kinase receptor blockade. Cancer Res 64:7977–7984

    Article  PubMed  CAS  Google Scholar 

  • Yokoi K, Sasaki T, Bucana CD, Fan D et al (2005) Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model. Cancer Res 65:10371–10380

    Article  PubMed  CAS  Google Scholar 

  • Younes MN, Yigitbasi OG, Park YW, Kim SJ et al (2005) Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation. Cancer Res 65:4716–4727

    Article  PubMed  CAS  Google Scholar 

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Hoekman, K., van Cruijsen, H., Giaccone, G. (2008). The EGF(R) and VEGF(R) Pathways as Combined Targets for Anti-Angiogenesis Trials in Cancer Therapy. In: Marmé, D., Fusenig, N. (eds) Tumor Angiogenesis. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-33177-3_39

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  • DOI: https://doi.org/10.1007/978-3-540-33177-3_39

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